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Abstract Background Cancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms. Methods We identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays. Results CircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties. Conclusions Our study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC. Graphical Abstract

Abstract Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2’s role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and β-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

Abstract Objective To study the historical global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035. Methods Incidence data were retrieved from the Cancer Incidence in Five Continents (CI5) volumes I-XI, and mortality data were obtained from the latest update of the World Health Organization (WHO) mortality database. We used join-point regression analysis to examine historical incidence and mortality trends and used the package NORDPRED in R to predict the number of deaths and mortality rates by 2035 by country and sex. Results More than 1,089,000 new cases of gastric cancer and 769,000 related deaths were reported in 2020. The average annual percent change (AAPC) in the incidence of gastric cancer from 2003 to 2012 among the male population, South Korea, Japan, Malta, Canada, Cyprus, and Switzerland showed an increasing trend (P > 0.05); among the female population, Canada [AAPC, 1.2; (95%Cl, 0.5–2), P 0.05). AAPC in the mortality of gastric cancer from 2006 to 2015 among the male population, Thailand [3.5 (95%cl, 1.6–5.4), P 0.05); among the male population aged 20–44, Thailand [AAPC, 3.4; (95%cl, 1.3–5.4), P 0.05). It is predicted that the mortality rate in Slovenia and France’s female population will show an increasing trend by 2035. It is predicted that the absolute number of deaths in the Israeli male population and in Chile, France, and Canada female population will increase by 2035. Conclusion In the past decade, the incidence and mortality of gastric cancer have shown a decreasing trend; however, there are still some countries showing an increasing trend, especially among populations younger than 45 years. Although mortality in most countries is predicted to decline by 2035, the absolute number of deaths due to gastric cancer may further increase due to population growth.

Abstract Robotic surgery may be an alternative to laparoscopic surgery for gastric cancer (GC). However, randomized controlled trials (RCTs) reporting the differences in survival between these two approaches are currently lacking. From September 2017 to January 2020, 300 patients with cT1-4a and N0/+ were enrolled and randomized to either the robotic (RDG) or laparoscopic distal gastrectomy (LDG) group (NCT03313700). The primary endpoint was 3-year disease-free survival (DFS); secondary endpoints reported here are the 3-year overall survival (OS) and recurrence patterns. The remaining secondary outcomes include intraoperative outcomes, postoperative recovery, quality of lymphadenectomy, and cost differences, which have previously been reported. There were 283 patients in the modified intention-to-treat analysis (RDG group: n = 141; LDG group: n = 142). The trial has met pre-specified endpoints. The 3-year DFS rates were 85.8% and 73.2% in the RDG and LDG groups, respectively (p = 0.011). Multivariable Cox regression model including age, tumor size, sex, ECOG PS, lymphovascular invasion, histology, pT stage, and pN stage showed that RDG was associated with better 3-year DFS (HR: 0.541; 95% CI: 0.314-0.932). The RDG also improved the 3-year cumulative recurrence rate (RDG vs. LDG: 12.1% vs. 21.1%; HR: 0.546, 95% CI: 0.302-0.990). Compared to LDG, RDG demonstrated non-inferiority in 3-year DFS rate.

Abstract Prospective evidence regarding the combination of programmed cell death (PD)−1 and angiogenesis inhibitors in treating locally advanced gastric cancer (LAGC) is limited. In this multicenter, randomized, phase 2 trial (NCT04195828), patients with gastric adenocarcinoma (clinical T2-4N + M0) were randomly assigned (1:1) to receive neoadjuvant camrelizumab and apatinib combined with nab-paclitaxel plus S-1 (CA-SAP) or chemotherapy SAP alone (SAP) for 3 cycles. The primary endpoint was the major pathological response (MPR), defined as

Abstract Background Chemoresistance is a major clinical challenge that leads to tumor metastasis and poor clinical outcome. The mechanisms underlying gastric cancer resistance to chemotherapy are still unclear. Methods We conducted bioinformatics analyses of publicly available patient datasets to establish an apoptotic phenotype and determine the key pathways and clinical significance. In vitro cell models, in vivo mouse models, and numerous molecular assays, including western blotting, qRT-PCR, immunohistochemical staining, and coimmunoprecipitation assays were used to clarify the role of factors related to apoptosis in gastric cancer in this study. Differences between datasets were analyzed using the Student’s t-test and two-way ANOVA; survival rates were estimated based on Kaplan–Meier analysis; and univariate and multivariate Cox proportional hazards models were used to evaluate prognostic factors. Results Bulk transcriptomic analysis of gastric cancer samples established an apoptotic phenotype. Proapoptotic tumors were enriched for DNA repair and immune inflammatory signaling and associated with improved prognosis and chemotherapeutic benefits. Functionally, cyclin-dependent kinase 5 (CDK5) promoted apoptosis of gastric cancer cells and sensitized cells and mice to oxaliplatin. Mechanistically, we demonstrate that CDK5 stabilizes DP1 through direct binding to DP1 and subsequent activation of E2F1 signaling. Clinicopathological analysis indicated that CDK5 depletion correlated with poor prognosis and chemoresistance in human gastric tumors. Conclusion Our findings reveal that CDK5 promotes cell apoptosis by stabilizing DP1 and activating E2F1 signaling, suggesting its potential role in the prognosis and therapeutic decisions for patients with gastric cancer.

Abstract Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, P

Abstract Background The long-term dynamic recurrence hazard of locally advanced gastric cancer (LAGC) in the clinical setting of adjuvant chemotherapy (ACT) remains unclear. Purpose This study aimed to investigate the dynamic recurrence risk of LAGC in patients who received ACT or not. Methods The study assessed data from patients with LAGC who underwent radical gastrectomy between January, 2010 and October, 2015. Inverse probability of treatment weighting (IPTW) was performed to reduce selection bias between the ACT and observational (OBS) groups. Conditional recurrence-free survival (cRFS) and restricted mean survival time (RMST) were used to assess the survival differences. Results In total, 1,661 LAGC patients were included (ACT group, n = 1,236 and OBS group, n = 425). The recurrence hazard gradually declined; in contrast, cRFS increased with RFS already accrued. Following IPTW adjustment, the cRFS rates were higher in the ACT group than those in the OBS group for patients at baseline or with accrued RFS of 1 and 2 years (p˂0.05). However, the cRFS rates of the ACT group were comparable with those of the OBS group for patients with accrued RFS of 3 or more years (p > 0.05). Likewise, the 5-year △RMST between the ACT and OBS groups demonstrated a similar trend. Moreover, the hematological metastasis rate of the ACT group was significantly lower than that of the OBS group for patients at baseline or with accrued RFS of 1 and 2 years, respectively (p˂0.05). Conclusions Although ACT could provide substantial benefits for patients with LAGC, the differences in recurrence hazard between the ACT and OBS groups may attenuate over time, which could help guide surveillance and alleviate patients’ anxiety. Further prospective large-scale studies are warranted.

ObjectiveTo explore the oncological outcomes of sequential laparoscopic gastrectomy after treatment with camrelizumab in combination with nab-paclitaxel plus S-1 for the treatment of gastric cancer with serosal invasion.MethodsThis study is a retrospective cohort study and retrospectively analyzed the clinicopathological data of 128 patients with serosal invasion gastric cancer (cT4NxM0) who received nab-paclitaxel + S-1(SAP) or camrelizumab + nab-paclitaxel + S-1 (C-SAP) regimen and underwent laparoscopy assisted gastrectomy in Fujian Union Hospital from March 2019 to December 2020. The patients were divided into SAP group and C-SAP group. The 2-years overall survival rate, 2-year recurrence free survival rate recurrence rate and initial recurrence time were compared between the two groups.ResultsA total of 128 patients were included, including 90 cases in SAP group and 38 cases in C-SAP group. There were no significant differences in age, gender, gastrectomy method, surgical approach, R0 resection, nerve invasion, vascular invasion, total number of harvested lymph nodes, number of positive lymph nodes and major pathologic response (MPR) rate between the two groups (P>0.05). However, the proportion of ypT0, ypN0 and pCR rate in C-SAP group were significantly higher than those in SAP group (P

Abstract The effectiveness of neoadjuvant immune checkpoint inhibitor (ICI) therapy is confirmed in clinical trials; however, the patients suitable for receiving this therapy remain unspecified. Previous studies have demonstrated that the tumor microenvironment (TME) dominates immunotherapy; therefore, an effective TME classification strategy is required. In this study, five crucial immunophenotype‐related molecules (WARS, UBE2L6, GZMB, BATF2, and LAG‐3) in the TME are determined in five public gastric cancer (GC) datasets (n = 1426) and an in‐house sequencing dataset (n = 79). Based on this, a GC immunophenotypic score (IPS) is constructed using the least absolute shrinkage and selection operator (LASSO) Cox, and randomSurvivalForest. IPSLow is characterized as immune‐activated, and IPSHigh is immune‐silenced. Data from seven centers (n = 1144) indicate that the IPS is a robust and independent biomarker for GC and superior to the AJCC stage. Furthermore, patients with an IPSLow and a combined positive score of ≥5 are likely to benefit from neoadjuvant anti‐PD‐1 therapy. In summary, the IPS can be a useful quantitative tool for immunophenotyping to improve clinical outcomes and provide a practical reference for implementing neoadjuvant ICI therapy for patients with GC.

Abstract LHPP, a histidine phosphatase, has been implicated in tumour progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Here, we obtained GC tissues and corresponding normal tissues from 48 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. The results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein levels. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. Together, our findings suggest that LHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

BackgroundImmune checkpoint inhibitors are increasingly used in neoadjuvant therapy for locally advanced gastric cancer. However, the effect of body composition on the efficacy of neoadjuvant therapy has not been reported.MethodsThe computed tomography (CT) images and clinicopathological data of 101 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy combined with immunotherapy (NCI) from 2019 to 2021 were collected. The CT image of L3 vertebral body section was selected, and the body composition before and after the neoadjuvant treatment was calculated using the SliceOmatic software, mainly including skeletal muscle index (SMI), subcutaneous adipose index (SAI), and visceral adipose index (VAI). The relationship between body composition and the efficacy and adverse events of NCI was analyzed.ResultsOf the 101 patients, 81 with evaluable data were included in the analysis. Of the included patients, 77.8% were male; the median age of all the patients was 62 years, and the median neoadjuvant therapy cycle was three. After the neoadjuvant therapy, 62.9% of the tumors were in remission (residual tumor cells ≤ 50%), and 37.1% of the tumors had no remission (residual tumor cells>50%). Moreover, 61.7% of the patients had treatment-related adverse events (TRAEs), and 18.5% had immune-related adverse events (irAEs). After neoadjuvant therapy, the body mass index (from 23 to 22.6 cm2/m2, p=0.042), SAI (from 34.7 to 32.9 cm2/m2, p=0.01) and VAI (from 32.4 to 26.8 cm2/m2, p=0.005) were significantly lower than those before treatment, while the SMI had no significant change (44.7 vs 42.5 cm2/m2, p=0.278). The multivariate logistics regression analysis revealed that low SMI (odds ratio [OR]: 3.23,95% confidence interval [CI]: 1.06–9.81, p=0.047), SMI attenuation (△SMI) ≥ 1.8(OR: 1.45,95%CI: 1.20–3.48, p=0.048), and clinical node positivity (OR: 6.99,95%CI: 2.35–20.82, p=0.001) were independent risk factors for non-remission. Additionally, high SAI is an independent risk factor for irAEs (OR: 14, 95%CI: 1.73–112.7, p=0.013).ConclusionLow SMI and △SMI≥1.8 are independent risk factors for poor tumor regression in patients with advanced gastric cancer receiving NCI. Patients with a high SAI are more likely to develop irAEs.

Objective: To assess the efficacy of Da Chaihu decoction combined with metformin tablets on patients with type 2 diabetes compared with metformin alone. Methods: This systematic review and meta‐analysis is written based on 2020 PRISMA Extension for Chinese Herbal Medicines 2020 (PRISMA-CHM 2020) reporting guidelines. We reviewed all the relevant studies from a search of the following databases from inception to February 2022 without any language restriction: Excerpta Medica Database (EMBASE), Google Scholar, PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Information, Wanfang Data, and the Chinese Biomedical Literature Database(CBM). Data were extracted and the quality was independently evaluated by two reviewers, based on the inclusion and exclusion criteria. Data were analyzed using the Cochrane software RevMan 5.3. Results: Six randomized controlled trials comprising 516 participants were included.The meta‐analysis revealed the Da Chaihu decoction combined with metformin tablets group was significantly superior to the metformin tablets group in terms of fasting blood glucose(FPG) (−0.66 mmol/L; 95 % CI (confidence intervals) [− 1.28, − 0.04]), plasma glucose 2 h after meal (2-h PG) (−1.18 mmol/L; 95 % CI [−1.94, −0.42]) in six RCTs, body mass index (BMI) (−3.07 mmol/L; 95 % CI [−6.89, 0.75]) in three RCTs, glycosylated hemoglobin (HbAlc) (−0.36 mmol/L; 95 % CI [−1.04, 0.31]) in three RCTs, and triglycerides (TG) (−0.76 mmol/L; 95 % CI [−1.37, −0.15]) in two RCTs. In two RCTs, there were significant differences in terms of total cholesterol (TC) (−0.97 mmol/L; 95 % CI [−1.18, −0.76]). Conclusions: Very low-quality research shows that Da Chaihu decoction combined with metformin tablets exert a certain level of efficacy on patients with type 2 diabetes compared with metformin alone. However, random sequence generation methodology was reported in five studies leading to the low quality of the included studies. None of the six studies depicted the blinding method, allocation concealment, selective reporting, and assessed the purity and potency of the product. This observation requires verification through high-quality, multi-center, double-blinded randomized controlled trials, and assesses the purity and potency of the product.

Abstract Background Application of indocyanine green (ICG) fluorescence imaging is effective in guiding laparoscopic radical lymphadenectomy for gastric cancer. However, the optimal approach for indocyanine green injection is controversial. Therefore, the objective of this study was aimed to compare the efficacy and ICG injection between the preoperative submucosal and intraoperative subserosal approaches for lymph node (LN) tracing during laparoscopic gastrectomy. Method This randomized controlled trial (ClinicalTrials.gov, NCT04219332) included 266 patients with potentially resectable gastric cancer (cT1–T4a, N0/+, M0) enrolled from a tertiary teaching center between December 2019 and October 2020. The primary endpoint was total number of retrieved LNs. Results In total, 259 patients (n = 130 and n = 129 in the submucosal and subserosal groups, respectively) were included in the per-protocol analysis. There are no significant differences in total number of retrieved LNs between the two groups (49.8 vs. 49.2, P = 0.713). The rate of LN noncompliance in the submucosal group was comparable to that in the subserosal group (32.3% vs. 33.3%, P = 0.860). No significant difference was found between the submucosal and subserosal groups in terms of the incidence (17.7% vs. 16.3%; P = 0.762) or severity of postoperative complications. The mean fluorescence cost in the submucosal group was higher than that in the subserosal group ($335.3 vs. $182.4; P < 0.001). The overall treatment satisfaction score was lower in the submucosal group than in the subserosal group (70.5 vs. 76.1%, P = 0.048). Conclusion ICG administered by subserosal injection was comparable to that administered by submucosal injection for lymph node tracing in gastric cancer. However, the former approach imposed a lower economic and mental burden on patients undergoing laparoscopic D2 lymphadenectomy. Trial registration ClinicalTrials.gov, NCT04219332 .

PurposeThe relationship between the CDK5RAP3 and UFM1 expression and the prolonged outcomes of patients who underwent gastric cancer (GC) surgery was investigated.MethodsSingle-sample gene set enrichment analysis (ssGSEA), unsupervised clustering and other methods were used to verify the relationship between CDK5RAP3 and UFM1 in GC through public databases. Additionally, CDK5RAP3 and UFM1 expression in cancerous and paracancerous tissues of GC was analysed in the context of patient prognosis.ResultsCDK5RAP3 and UFM1 expression was downregulated synchronously, the interaction was observed between the two proteins, and UFM1 and CDK5RAP3 expression was found to be inversely associated to AKT pathway activation. Prognostic analysis showed that the prognosis is poorer for low CDK5RAP3 and UFM1 patients, than for high CDK5RAP3 and/or UFM1 (p

BackgroundFew studies have reported the association of early life exposure to famine with the risk of heart failure. The current study aimed to investigate whether exposure to famine in early life is associated with a higher risk of hospitalization for heart failure in adulthood.MethodsWe used data from participants included in the sub-cohort of the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project in Guangdong Province. Specific years of birth were used to define the famine-exposed group (born during the famine of 1959–1962), the pre-famine group (born before the famine [1954–1957], and the post-famine group (born after the famine [1964–1967]). Multivariable-adjusted generalized linear models were used to examine the associations of early life famine exposure with the risk of hospitalization for heart failure.ResultsA total of 36,212 participants were enrolled in this analysis with a median age of 57.4 years and 37.5% of them were men. Compared with the post-famine group, famine births and pre-famine births were associated with increased risk of heart failure (OR: 1.96 [1.56–2.48] and OR: 1.62 [1.07–2.47], respectively). When compared with the age-balanced non-exposed group, the famine-exposed group was also significantly associated with increased risk of heart failure (OR: 1.32 [1.11–1.57]). The associations were stronger in participants with better economic status and in participants with hypertension, diabetes, and dyslipidemia (P for interaction < 0.05).ConclusionEarly life exposure to the Chinese famine is associated with an elevated risk of hospitalization for heart failure in adulthood.

Background: Compared with other histologic types, signet ring cell gastric carcinoma (SRC) has unique oncological characteristics, and its implication on the prognosis of gastric cancer patients remains unclear. The purpose of this study was to evaluate the prognostic impact of body mass index (BMI) on SRC patients. Methods: A retrospective analysis was performed using the clinical records of 3342 patients with SRC or tubular adenocarcinoma who underwent radical gastrectomy between 2000 and 2014. Patients were divided into three groups according to histologic subtype: SRC, well-to-moderately differentiated adenocarcinoma (WMD), and poorly differentiated adenocarcinoma (PD). We compared the survival of SRC patients with that of tubular adenocarcinoma patients according to BMI. Results: The 5-year survival of SRC was significantly worse than that of WMD (P 0.05) and better than that of PD (P

Expression patterns of immune checkpoints in patients with gastric cancer remain poorly characterized. Here the authors propose an immune scoring system based on the expression of six immunosuppressive ligands to improve the prognostic accuracy in gastric cancer patients and drive the selection of candidates for adjuvant chemotherapy.

Abstract Background The relationship between sarcopenia and the prognoses of patients with gastric neuroendocrine neoplasms (g-NENs) is unclear. This study was designed to explore the effects of sarcopenia on short-term and long-term outcomes of patients with g-NENs after radical gastrectomy. Methods This study retrospectively collected data from 138 patients with g-NENs after radical gastrectomy. The skeletal muscle index (SMI) diagnostic threshold for sarcopenia was determined using X-tile software. Cox regression analyses were performed to determine the independent risk factors for 3-year overall survival (OS) and 3-year recurrence-free survival (RFS). Results In this study, 59 patients (42.8%) were diagnosed with sarcopenia. Among patients in the sarcopenia group and nonsarcopenia group, the incidences of total postoperative complications were 33.9 and 30.4%, incidences of serious postoperative complications were 0 and 3.7%, incidences of postoperative surgical complications were 13.6 and 15.2%, and incidences of postoperative systemic complications were 20.3 and 15.2%, respectively (all p > 0.05). The 3-year OS and RFS rates were significantly worse in the sarcopenia group than in the nonsarcopenia group (OS: 42.37% vs 65.82%, p = 0.004; RFS: 52.54% vs 68.35%, p = 0.036). The multivariate analysis revealed a relation between sarcopenia and the long-term prognoses of patients with g-NENs. A stratified analysis based on the pathological type revealed that the Kaplan-Meier curve was only significantly different in patients with gastric mixed adenoneuroendocrine carcinoma (gMANEC) (OS: 40.00% vs 71.79%, p = 0.007; RFS: 51.43% vs 74.36%, p = 0.026); furthermore, the multivariate analysis identified sarcopenia as an independent risk factor for patients with gMANEC (p

Abstract Background BATF2, also known as SARI, has been implicated in tumor progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Methods We obtained GC tissues and corresponding normal tissues from 8 patients and identified BATF2 as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine BATF2 levels in normal and GC tissues. The prognostic value of BATF2 was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of BATF2 in GC growth and metastasis were evaluated in vitro and in vivo. Results BATF2 expression was significantly decreased in GC tissues at both the mRNA and protein level. Multivariate Cox regression analysis revealed that BATF2 was an independent prognostic factor and effective predictor in patients with GC. Low BATF2 expression was remarkably associated with peritoneal recurrence after curative gastrectomy. Moreover, elevated BATF2 expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, BATF2 binds to p53 and enhances its protein stability, thereby inhibiting the phosphorylation of ERK. Tissue microarray results indicated that the prognostic value of BATF2 was dependent on ERK activity. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA by METTL3 repressed its expression in GC. Conclusions Collectively, our findings indicate the pivotal role of BATF2 in GC and highlight the regulatory function of the METTL3/BATF2/p53/ERK axis in modulating GC progression, which provides potential prognostic and therapeutic targets for GC treatment.

Abstract Background Many studies have found that use of aspirin can lengthen survival in patients with gastrointestinal cancer. The aim of this study was to assess the survival benefit of aspirin use compared with non-aspirin use for patients with esophageal, gastric or colorectal cancer. Methods We searched online databases, including PubMed, the Cochrane Library, Embase and www.clinicaltrials.gov for studies that were conducted, before April 30th, 2020, to identify relevant studies. Overall survival and cancer-specific survival of esophageal, gastric and colorectal cancers among aspirin users were compared with those among non-aspirin users. Data extraction and quality evaluation were independently conducted by 2 investigators. A meta-analysis was performed to calculate the pooled risk ratios (RRs) for overall survival and cancer-specific survival by using either a fixed-effects model or a random-effects model. Results A total of 18 studies were included in this meta-analysis, with more than 74,936 patients. There were no significant differences between postdiagnosis aspirin use and overall survival for esophageal and gastric cancers. For colorectal cancer, a benefit that was associated with postdiagnosis aspirin use was observed for overall survival and cancer-specific survival [HR = 0.83, 95%CI(0.75, 0.9.);HR = 0.78, 95%CI(0.66, 0.92), respectively. However, a prediagnosis of aspirin use did not provide a benefit for overall or cancer-specific survival in colorectal cancer. HR values for overall and cancer-specific survival benefits for colorectal cancer associated with both prediagnosis and postdiagnosis aspirin were as follows: HR = 0.75, 95%CI(0.61, 0.92) and HR = 0.78, 95%CI(0.73, 0.85), respectively. In addition, the survival benefit of postdiagnosis aspirin use appeared to be confined to patients with mutated PIK3CA tumors [HR = 0.78, 95%CI(0.50, 0.99)] and was positive for PTGS2 (COX-2) expression [HR = 0.75, 95%CI(0.43, 1.30)]. Conclusions These findings provide further indications that postdiagnosis aspirin use improves overall survival and cancer-specific survival in colorectal cancer, especially for patients who are positive for PTGS2 (COX-2) expression and PIK3CA-mutated tumors. However, aspirin therapy does not improve overall survival in esophageal and gastric cancers, although the meta-analysis was mainly limited to retrospective studies.

Abstract Background We sought to investigate the prognostic value of complete blood count (CBC)-based biomarkers for patients with resectable gastric cancer (GC). Methods Patients with GC who underwent primary surgical resection between December 2008 and December 2013 were included. The estimated area under the curve (AUC) and multivariate Cox regression models were used to identify the best CBC-based biomarker. Time-dependent receiver operating characteristic (t-ROC) curve analysis was used to predict overall survival and compare the prognostic impact. Results In the 1810 patients analyzed, the median follow-up period was 51.0 months (range 1–101 months). Based on multivariate analysis, the lymphocyte-monocyte ratio (LMR) and hemoglobin (Hb) level were independent prognostic factors (both P

ObjectiveTo investigate the safety and efficacy of camrelizumab in combination with nab-paclitaxel plus S-1 for the treatment of gastric cancer with serosal invasion.MethodTwo hundred patients with gastric cancer with serosal invasion who received neoadjuvant therapy from January 2012 to December 2020 were retrospectively analyzed. According to the different neoadjuvant therapy regimens, the patients were divided into the following three groups: the SOX group (S-1 + oxaliplatin) (72 patients), SAP group (S-1 + nab-paclitaxel) (95 patients) and C-SAP group (camrelizumab + S-1 + nab-paclitaxel) (33 patients).ResultThe pathological response (TRG 1a/1b) in the C-SAP group (39.4%) was not significantly different from that in the SAP group (26.3%) and was significantly higher than that in the SOX group (18.1%). The rate of ypT0 in the C-SAP group (24.2%) was higher than that in the SAP group (6.3%) and the SOX group (5.6%). The rate of ypN0 in the C-SAP group (66.7%) was also higher than that in the SAP group (38.9%) and the SOX group (36.1%). The rate of pCR in the C-SAP group (21.2%) was higher than that in the SAP group (5.3%) and the SOX group (2.8%). The use of an anti-PD-1 monoclonal antibody was an independent protective factor for TRG grade (1a/1b). The use of camrelizumab did not increase postoperative complications or the adverse effects of neoadjuvant therapy.ConclusionCamrelizumab combined with nab-paclitaxel plus S-1 could significantly improve the rate of tumor regression grade (TRG 1a/1b) and the rate of pCR in gastric cancer with serosal invasion.

Abstract Purpose To determine the indications for adjuvant chemotherapy (AC) in patients with stage IIa gastric cancer (T3N0M0 and T1N2M0) according to the 7th American Joint Committee on Cancer (AJCC). Methods A total of 1593 patients with T3N0M0 or T1N2M0 stage gastric cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database for the period 1988.1–2012.12. Cox multiple regression, nomogram and decision curve analyses were performed. External validation was performed using databases of the Fujian Medical University Union Hospital (FJUUH) (n = 241) and Italy IMIGASTRIC center (n = 45). Results Cox multiple regression analysis showed that the risk factors that affected OS in patients receiving AC were age > 65 years old, T1N2M0, LN dissection number ≤ 15, tumor size > 20 mm, and nonadenocarcinoma. A nomogram was constructed to predict 5-year OS, and the patients were divided into those predicted to receive a high benefit (points ≤ 188) or a low benefit from AC (points > 188) according to a recursive partitioning analysis. OS was significantly higher for the high-benefit patients in the SEER database and the FJUUH dataset than in the non-AC patients (Log-rank

BackgroundThe efficacy and benefits of adjuvant chemotherapy (AC) for patients with gastric cancer pT3N0M0 remain controversial.MethodsWe prospectively collected and retrospectively analyzed 235 patients with pT3N0M0 gastric cancer who underwent radical resection between February 2010 and January 2016. Patients were divided into two groups: the surgery-alone (SA) group (n = 82) and the AC group (n = 153). We analyzed the effects of AC on the overall survival (OS) and recurrence-free survival (RFS), and the relationship between the number of chemotherapy cycles (CC) and recurrence rate (RR).ResultsThe 5-year OS and RFS of the participants were 80.9% and 87.7%, respectively, and those in the AC group were significantly higher than those in the SA group (86.9% vs. 69.5%, p = 0.003). The RFS of the AC and SA groups were 88.9% and 85.4%, respectively; the difference was not statistically significant (p = 0.35). The independent risk factors affecting the OS were perineural invasion-positive (PNI+) (HR = 2.64, 95%CI: 1.45–4.82, p = 0.003) and age ≥ 65 years (HR = 2.58, 95%CI: 1.39–4.8, p = 0.003). The independent risk factor affecting the RFS was also PNI+ (HR3.11; 95%CI: 1.48–6.54, p = 0.003). Stratified analysis revealed that postoperative AC can significantly improve the OS of PNI+ patients (AC group versus SA group: 84.1% vs. 45.5%, p = 0.001) and RFS (86.4% vs. 63.6%, p = 0.017). However, perineural invasion negative (PNI-) patients did not show the same results (p = 0.13 and p = 0.48, respectively). According to the number of CC, divided into CC < 3 groups and CC ≥ 3 groups, the cumulative RR in the CC ≥ 3 group of patients with PNI+ was significantly lower than that of the CC < 3 group (7.4% vs. 28.2%, p = 0.037).ConclusionFor pT3N0M0 gastric cancer patients with PNI+, at least three cycles of postoperative AC can significantly reduce the overall RR. This finding should be verified by using large external sample data.

ObjectiveTo validate the prognostic value of tumor regression grading (TRG) and to explore the associated factors of TRG for advanced gastric cancer (AGC) with neoadjuvant chemotherapy (NACT) plus surgery.MethodsTwo hundred forty-nine AGC patients treated with NACT followed by gastrectomy at the Mayo Clinic, USA and the Fujian Medical University Union Hospital, China between January 2000 and December 2016 were enrolled in this study. Cox regression was used to identify covariates associated with overall survival (OS) and recurrence-free survival (RFS). Logistic regression was used to reveal factors predicting tumor regression grading.ResultsFor patients with TRG 0-1, the 3- and 5-year OS rates were 85.2% and 74.5%, respectively, when compared to 56.1% and 44.1% in patients with TRG 2 and 28.2% and 23.0% in patients with TRG 3, respectively (p

Abstract Background The platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and neutrophil to lymphocyte ratio (NLR) reflect the systematic inflammatory response, with some evidence revealing that they are associated with poorer survival in patients with gastric cancer. However, the effect of the white blood cell to hemoglobin ratio (WHR) on the long-term prognosis of patients with gastric cancer has not been reported. Therefore, we sought to characterize the effect of WHR on long-term survival after radical gastrectomy and compare its value with that of other preoperative inflammation-based prognostic scores (PIPS). Methods Data from 924 patients with a diagnosis of nonmetastatic gastric adenocarcinoma who underwent surgical resection between December 2009 and May 2013 were included in this study. Results The optimal cutoff values for the WHR, PLR, LMR, and NLR were 2.855, 133.03, 3.405, and 2.61, respectively. Patients with an increased WHR (53% vs. 88.1%, p

Abstract Background Most lymph node metastasis (LNM) models for early gastric cancer (EGC) include lymphovascular invasion (LVI) as a predictor. However, LVI must be confirmed by postoperative pathology. In this study, we aimed to develop a model for predicting the risk of LNM/LVI in EGC using preoperative factors. Methods EGC patients who underwent radical gastrectomy at Fujian Medical University Union Hospital and Sun Yat-sen University Cancer Center (n = 1460) were selected as the training set. The risk factors of LNM/LVI were investigated. Data from the International study group on Minimally Invasive surgery for GASTRIc Cancer trial (n = 172) were selected as the validation set. Results In the training set, the incidence of LNM/LVI was 21.6%. The 5-year cancer-specific survival rates of patients with and without LNM/LVI were 92.4 and 95.0%, respectively, with significant difference (P = 0.030). Multivariable logistic regression analysis showed that the four independent risk factors for LNM/LVI were female, tumor larger than 20 mm, submucosal invasion and undifferentiated tumor histological type (all P

Abstract Background Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date. Methods Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3′s effect on angiogenesis. Results Compared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1α/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis. Conclusions This study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.

Abstract Background UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. Methods Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique. Results Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P

Abstract Background This study investigated a large number of patients to develop a predictive nomogram for survival and a web-based survival rate calculator that can dynamically predict the long-term survival of patients with primary gastric diffuse large B-cell lymphoma. Methods A total of 2647 patients diagnosed with primary gastric diffuse large B-cell lymphoma from 1998 to 2014 were extracted from the SEER database. We used the Lasso Cox regression model to identify independent risk factors for long-term survival and to develop a predictive nomogram for survival and a web-based survival rate calculator. Results The median (mean) follow-up time was 30 months (52.8 months). Cancer-specific survival rates decreased with time, while the 5-year conditional survival increased with time. Cancer-specific deaths were not constant. Cancer-specific deaths of patients within the first 2 years were high, while the risk remained relatively constant after 2 years. The independent risk factors included surgery, chemotherapy, tumor stage and age, according to the Lasso Cox regression analysis. We developed a predictive nomogram and a web-based survival rate calculator (https://linjuli1991.shinyapps.io/dynnomapp/). The calibration plot suggested that the actual value exhibited good agreement with the predicted value. Conclusions We found that patients with primary gastric diffuse large B-cell lymphoma had a high risk of death during the first 2 years. Additional active follow-up strategies should be provided during this period. This is the first study to develop a predictive nomogram and a web-based survival rate calculator that can provide evidence for individual treatment and follow-up.

Abstract Background Tumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Methods Using a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining. Results Compared with CD8+ TIL-negative cases (n = 196, 48.6%), CD8+ TIL-positive cases (n = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank p

Summary: To identify the risk factors for intraoperative laparoscopic hemostasis during laparoscopic spleen-preserving splenic hilar lymph node dissection (LSPSD) for proximal gastric cancer (GC) and to develop and validate a model to estimate the risk of intraoperative laparoscopic hemostasis.Between January 2011 and December 2014, we prospectively collected and retrospectively analyzed the medical records of 398 patients with proximal GC who underwent LSPSD. The data were split 75/25, with one group used for model development and the other for validation testing.Of the 398 patients enrolled in this study, 174 (43.7%) required laparoscopic hemostasis treatment. A multivariate analysis determined that the risk factors for the model group were gender, preoperative N stage, and terminal branches of the splenic artery (SpA), and each factor contributed 1 point to the risk score. The intraoperative laparoscopic hemostasis rates were 11.5%, 33.6%, 58.5%, and 73.5% for the low-, intermediate-, high-, and extremely high-risk categories, respectively (p

Abstract Background Whether the tumor‐node‐metastasis (TNM) staging system is appropriate for patients with node‐negative gastric cancer (GC) is still inconclusive. The modified staging system developed by recursive partitioning analysis (RPA) showed good prognostic performance in a variety of cancers. The application of RPA has not been reported in the prognostic prediction of GC. Methods Node‐negative GC patients who underwent radical resection at Fujian Medical University Union Hospital (n = 862) and Sun Yat‐sen University Cancer Center (n = 311) with at least 5 years of follow‐up were selected as the training set. RPA was used to develop a modified staging system. Patients from the Surveillance, Epidemiology, and End Results database (n = 1415) were selected as the validation set. Results The 5‐year overall survival (OS) rates of patients with 8th AJCC‐TNM stage IA‐IIIA in the training set were IA 95.2%, IB 87.1%, IIA 78.3%, IIB 75.8%, and IIIA 72.6%. Multivariate analysis (MVA) showed that larger tumor size, elder age, and deeper depth of invasion were independent predictors for OS in patients with node‐negative GC (all P

Abstract Introduction To assess the ability of the Age-Adjusted Charlson Comorbidity Index (ACCI) to predict survival after radical gastrectomy in patients with gastric cancer (GC). Method Data from patients with GC who underwent radical gastrectomy from January 2008 to December 2012 in Fujian Medical University Union Hospital were retrospectively analyzed. Patients were categorized into either high ACCI group or low ACCI group based on the effect of ACCI on long-term GC prognosis. 1:1 propensity score matching (PSM) was used to reduce confounding bias. To further analyze the impact of ACCI on the long-term prognosis of patients after radical gastrectomy, a nomogram was built based on the Cox proportional hazards regression model. Results A total of 1476 patients were included in the analysis. After PSM, there was no statistically significant differences in tumor location, tumor size and tumor stage between low ACCI group (429 cases) and high ACCI group (429 cases) (all P > 0.05). Before and after PSM, the incidence of postoperative complications in high ACCI group was significantly higher than that in low ACCI group (P

Abstract Background This study sought to explore whether lymphovascular invasion can affect the prognosis of patients with stage N0 gastric cancer and to evaluate the survival benefit of adjuvant chemotherapy for such patients. Method From January 2006 to December 2011, a total of 2102 gastric cancer patients undergoing radical gastric resection were enrolled in this study. Homogeneity, discriminatory ability, and monotonicity of gradients in the combination of lymphovascular invasion and the 8th edition of the AJCC staging system and the 8th edition of the AJCC staging system alone were compared using linear trend χ2, likelihood ratio χ2 statistics, and Akaike information criterion (AIC) calculations. The Kaplan-Meier method and the log-rank test were used to analyze between-group differences in survival rate. Result The median follow-up time of the whole group was 58 months, and the average age of the whole group was 63.9 years (range 21–89 years). The 3-year and 5-year overall survival rates in N0 patients with lymphovascular invasion were lower than those in N0 patients without lymphovascular invasion (3-year OS: 78.3% vs 92.5%, 5-year OS: 70.0% vs 88.3%, p

Abstract Background Little is known about the correlation between the clinicopathological features, postoperative treatment, and prognosis of multiple gastric cancers (MGCs). In this study, we aimed to investigate the correlation between these features and the impact of postoperative adjuvant chemotherapy on the long-term survival of patients with MGC. Methods The clinical and pathological data of patients diagnosed with gastric adenocarcinoma who had radical gastrectomy from January 2007 to December 2016 were analyzed. Using propensity score matching, the prognostic differences, and the impact of postoperative adjuvant chemotherapy between those with MGC and solitary gastric cancers (SGC) were compared. Results Among the 4107 patients investigated, the incidence of MGC was 3.2% (133/4107). Before matching, patients with MGC and SGC had disparities in the type of gastrectomy, pathological tumor stage (pT), pathological node stage (pN), and pathological tumor-node-metastasis stage (pTNM). After a 1:4 ratio matching, the clinical data of 133 cases of MGC and 532 cases of SGC were found to be comparable. The 5-year overall survival (OS) rate was 56.6% in the entire matched cohort, 48.1% in the MGC group, and 58.7% in the SGC group (P = 0.013). Multivariate analysis revealed that MGC, age, pT stage, pN stage, and adjuvant chemotherapy were independent predictors of OS (all P

Abstract Background The eighth TNM classification for gastric cancer categorizes N3 as N3a and N3b in the final pathologic stage. The cutoff for N3a/N3b is defined as 15 metastatic lymph nodes, but the rationale for this cutoff remains unclear. This study aimed to determine the optimal N3a/N3b cutoff and evaluate its prognostic significance. Methods An international database was constructed by combining data from patients with N3 gastric cancer and complete five-year follow-up data from the Surveillance, Epidemiology, and End Results program database (n = 1833) and the Fujian Medical University Union Hospital database (n = 920) (total n = 2753). A log-rank test was performed to determine the optimal N3a/N3b cutoff, and its prognostic significance was confirmed in a two-step multivariate analysis and compared to that of the eighth TNM. Results A cut-point analysis performed at each metastatic lymph node number identified the greatest survival difference between N3a and N3b at 13 metastatic lymph nodes (χ2 = 157.671, P = 3.65 × 10− 36). In patients with 14–15 metastatic lymph nodes, prognoses were significantly worse than those in patients with 7–13 metastatic lymph nodes (P 15 metastatic lymph nodes (P = 0.078). Therefore, patients with 14–15 metastatic lymph nodes were incorporated into a modified N3b classification. In the two-step multivariate analysis, the eighth N3 classification fell out of the model, while the modified N3 classification remained intact (HR 1.51, P

Background: The benefit of adjuvant chemotherapy varies widely among patients with stage II/III gastric cancer (GC), and tools predicting outcomes for this patient subset are lacking. We aimed to develop and validate a nomogram to predict recurrence-free survival (RFS) and the benefits of adjuvant chemotherapy after radical resection in patients with stage II/III GC.Methods: Data on patients with stage II/III GC who underwent R0 resection from January 2010 to August 2014 at Fujian Medical University Union Hospital (FMUUH) (n = 1,240; training cohort) were analyzed by Cox regression to identify independent prognostic factors for RFS. A nomogram including these factors was internally and externally validated in FMUUH (n = 306) and a US cohort (n = 111), respectively.Results: The multivariable analysis identified age, differentiation, tumor size, number of examined lymph nodes, pT stage, pN stage, and adjuvant chemotherapy as associated with RFS. A nomogram including the above 7 factors was significantly more accurate in predicting RFS compared with the 8th AJCC-TNM staging system for patients in the training cohort. The risk of peritoneal metastasis was higher and survival after recurrence was significantly worse among patients calculated by the nomogram to be at high risk than those at low risk. The nomogram's predictive performance was confirmed in both the internal and external validation cohorts.Conclusion: A novel nomogram is available as a web-based tool and accurately predicts long-term RFS for GC after radical resection. The tool can also be used to determine the benefit of adjuvant chemotherapy by comparing scores with and without this intervention.

Background and Objective: No specialized prognostic model for patients with gastric cancer with peritoneal metastasis (GCPM) exists for intraoperative clinical decision making. This study aims to establish a new prognostic model to provide individual treatment decisions for patients with GCPM.Method: This retrospective analysis included 324 patients with GCPM diagnosed pathologically by laparoscopy from January 2007 to January 2018 who were randomly assigned to different sets (227 in the training set and 97 in the internal validation set). A nomogram was established from preoperative and intraoperative variables determined by a Cox model. The predictive ability and clinical applicability of the PM nomogram (PMN) were compared with the 15th Japanese Classification of Gastric Carcinoma (JCGC) Staging Guidelines for PM (P1abc). Additional external validation was performed using a dataset (n = 39) from the First Affiliated Hospital of University of Science and Technology of China.Results: The median survival time was 8 (range, 1–90) months. In the training set, each PMN substage had significantly different survival curves (P < 0.001), and the PMN was superior to the P1abc based on the results of time-dependent receiver operating characteristic curve, C-index, Akaike information criterion and likelihood ratio chi-square analyses. In the internal and external validation sets, the PMN was also better than the P1abc in terms of its predictive ability. Of the PMN1 patients, those undergoing palliative resection had better overall survival (OS) than those undergoing exploratory surgery (P < 0.05). Among the patients undergoing exploratory surgery, those who received chemotherapy exhibited better OS than those who did not (P < 0.05). Among the patients who received palliative resection, only PMN1 patients exhibited better OS following chemotherapy (P < 0.05).Conclusion: We developed and validated a simple, specific PM model for patients with GCPM that can predict prognosis well and guide treatment decisions.

Background: To investigate the prognostic effects and risk factors of the omission and delay of postoperative chemotherapy of stage II/III gastric cancer (GC).Methods: The clinicopathological data of 1,520 patients undergoing radical gastrectomy for stage II/III GC were collected and retrospectively analyzed. We defined the chemotherapy delayed until more than 60 days after radical gastrectomy and the complete omission of chemotherapy as unacceptable chemotherapy initiation (UAC), whereas the chemotherapy conducted within 60 days of radical gastrectomy was defined as acceptable chemotherapy initiation (AC). The survival between the two groups was compared, and the trends and risk factors of UAC were analyzed.Results: There were 539 (35.5%) patients with UAC. The overall survival (OS) and disease-free survival of the UAC group patients were significantly inferior to those in the AC group (p < 0.001). Cox multivariate analysis demonstrated that UAC is an independent predictor of OS (p < 0.05). The OS and disease-free survival of the patients in the UAC group were close to those of the patients without chemotherapy (p > 0.05). Logistic analysis showed that female, old age, a self-paid status, a very low social status, high American Society of Anesthesiologists scores, intra-abdominal surgery history, and serious postoperative complications were independent risk factors of UAC (all p < 0.05). The radar chart shows the risk factors of UAC changed with time.Conclusions: UAC after radical gastrectomy is an independent risk factor for the prognosis of stage II/III GC patients. However, no significant decline of UAC has been achieved recently and should call for the attention of both government and clinicians.

Abstract Background The types of patients with gastric adenocarcinoma (GA) for whom postoperative radiotherapy can improve the disease-specific survival rate (DSS) remain controversial. This study aims to explore the ideal indications. Methods Patients in the Surveillance, Epidemiology, and End Results (SEER) database with T3–4Nx or TxN+ GA from January 1988 to December 2012 were included and divided into a postoperative chemoradiotherapy group (Group R) and a postoperative chemotherapy group (Group C). We established a nomogram to predict DSS and then divided entire patient cohort into low-risk and high-risk groups based on the DSS predicted by the nomogram. Results The Cox multiple regression analysis demonstrated that various risk factors affected DSS for Group R. Based on these risk factors, a nomogram for predicting DSS was established. The decision curve indicated that the best clinical effect could be obtained when the threshold probability was 0–58%. The patients were then divided into low-risk (

Abstract Background To assess the prognostic factors and investigate the optimal treatment of gastric mixed adenoneuroendocrine tumors. Methods We retrospectively analyzed clinical data from 80 patients with gastric mixed adenoneuroendocrine carcinoma that received radical resection in our department from January 2007 to December 2016. Risk factors for relapse and survival were analyzed using a multivariate Cox proportional hazards regression model. Gastric mixed adenoneuroendocrine carcinoma was divided into neuroendocrine carcinoma and adenocarcinoma based on the predominant type in the tumor. Results The 3-year overall survival was 40% in the neuroendocrine carcinoma group and 75% in the adenocarcinoma group (P = 0.006). The neuroendocrine carcinoma (NEC)-dominant tumors and a Ki-67-positive index ≥60% were independent risk factors for worse overall survival. The 3-year recurrence-free survival was 33% in the neuroendocrine carcinoma group and 68% in the adenocarcinoma group. NEC-dominant tumors and a Ki-67-positive index ≥60% were independent risk factors for gastric mixed adenoneuroendocrine carcinoma recurrence. Patients in the adenocarcinoma group that received adjuvant chemotherapy exhibited significantly better overall survival than patients that did not receive chemotherapy (median survival time 43 months vs. 13 months, P = 0.026). Conclusion The NEC-dominant tumors and a Ki-67-positive index ≥60% were significantly associated with worse survival and a higher recurrence rate for gastric mixed adenoneuroendocrine carcinoma patients. Patients in the adenocarcinoma group may benefit from gastric adenocarcinoma treatments.

Abstract Given the rarity and indolent clinical course of gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), conditional survival might be the most suitable parameter for cancer survivors who wish to receive accurate prognostic information during follow‐up. We have explored the updated incidence trend and the conditional survival of patients with GEP‐NETs. Incidence trends from 2000 to 2014 were determined through an assessment of patients in the SEER cancer registry. Patients diagnosed between 1988 and 2011 were included in the conditional survival analysis, and the 3‐year conditional cancer‐specific survival (CCS3) was computed. The incidence of GEP‐NETs, which is far higher than the incidence of many malignant tumors, is still increasing steadily (annual percentage change = 4.4). The risk of death from NETs is dynamic over time, and most deaths occur in the first 3 years after diagnosis. Patients with gastric, rectal, or appendiceal NETs hardly exhibit any excess mortality (CCS3 > 95%) given that they have already survived until a defined time‐point within 10 years. The initial difference between each age group basically disappeared with an extension of the survival time since the initial diagnosis of gastric, appendiceal, or rectal NETs, but the difference persisted for tumors at other sites. Although patients with advanced‐stage or higher‐grade tumors have a worse survival at diagnosis than patients with early‐stage or lower‐grade tumors, the difference diminishes and might even disappear over time. For GEP‐NETs that are rare but exhibit slow growth, clinically relevant variations in conditional survival were observed based on the time since diagnosis. Therefore, conditional survival can serve as a guideline that can be used by cancer survivors to plan their future and doctors to plan surveillance schedules.

Owing to the spread of multidrug resistance (MDR) and extensive drug resistance (XDR), there is a pressing need to identify potential targets for the development of more-effective anti-M. tuberculosis (Mtb) drugs. PafA, as the sole Prokaryotic Ubiquitin-like Protein ligase in the Pup-proteasome System (PPS) of Mtb, is an attractive drug target. Here, we show that the activity of purified Mtb PafA is significantly inhibited upon the association of AEBSF (4-(2-aminoethyl) benzenesulfonyl fluoride) to PafA residue Serine 119 (S119). Mutation of S119 to amino acids that resemble AEBSF has similar inhibitory effects on the activity of purified Mtb PafA. Structural analysis reveals that although S119 is distant from the PafA catalytic site, it is located at a critical position in the groove where PafA binds the C-terminal region of Pup. Phenotypic studies demonstrate that S119 plays critical roles in the function of Mtb PafA when tested in M. smegmatis. Our study suggests that targeting S119 is a promising direction for developing an inhibitor of M. tuberculosis PafA. Keywords: M. Tuberculosis, Pupylation, PafA, 4-(2-aminoethyl) benzenesulfonyl fluoride

Abstract Background CDK5RAP3 was initially isolated as a binding protein of the CDK5 activator p35. Although CDK5RAP3 has been shown to negatively regulate the Wnt/β-catenin signaling pathway in gastric cancer by repressing GSK-3β phosphorylation, its in-depth mechanism has not been determined. Methods Following CDK5RAP3 overexpression or knock down, CDK5RAP3 signaling pathways were investigated in gastric cancer cells by Western Blotting. Cell growth, invasion and migration were also evaluated in gastric cancer cell lines. We analyzed CDK5RAP3, AKT, p-AKT (Ser473), GSK-3β and p-GSK-3β (Ser9) expression in gastric tumor samples and adjacent non-tumor tissues from 295 patients using immunohistochemistry and Western Blotting. The prognostic significance of CDK5RAP3 and p-AKT (Ser473) was confirmed by a Log-rank test. Results Our study demonstrated that the expression of p-AKT (Ser473) and p-GSK-3β (Ser9) was negatively correlated with CDK5RAP3 in stable gastric cancer cell lines. CDK5RAP3 repressed AKT phosphorylation, which promoted GSK-3β phosphorylation, thereby suppressing β-catenin protein expression and, consequently, gastric cancer. The protein level of CDK5RAP3 was markedly decreased in most gastric tumor tissues compared with adjacent non-tumor tissues, and the levels of p-AKT (Ser473) and p-GSK-3β (Ser9) were also negatively correlated with those of CDK5RAP3. The prognostic value of CDK5RAP3 for overall survival was found to be dependent on AKT phosphorylation. Conclusion Our results demonstrated that CDK5RAP3 negatively regulates the Wnt/β-catenin signaling pathway by repressing AKT phosphorylation, which leads to better survival of patients with gastric cancer.

Abstract Background The presence and the prognostic significance of perigastric tumor deposits (TDs) in primary gastric cancer have not been extensively studied. The aim of this study was to evaluate the prognostic significance perigastric TDs in primary gastric cancer. Methods From 2005 to 2010, 1250 patients underwent R0 gastrectomy at the Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China. Out of 1250 patients, 132 patients with perigastric TDs were identified. Additionally, 132 patients with staged matched gastric cancer without tumor deposits were selected as a control group. Results Perigastric TDs were observed in 132 (10.5%) of the 1250 patients with gastric cancer who underwent R0 gastrectomy. There were 94 males (71.21%) and 38 females (28.79%) (2.47:1). The mean age was 57.21 years. Clinicopathologic characteristics between the two groups matched well. There was a significant difference in the overall survival of those with and without TDs by univariate (p0.05); however, when comparing each pT tumor group with the perigastric TD group, the stage T4 survival rate was very similar to that observed in patients with TDs. Conclusions Perigastric TDs are an independent predictive prognostic factor for gastric cancer and may be appropriately considered a form of serosal invasion. We suggest that TDs should be included in TNM staging system for better outcomes.

Background. The aim of this retrospective study was to compare the long-term survival of patients receiving conservative with surgical treatment to analyze the prognostic factors and the impact of surgery on oncological outcomes of patients with primary gastric diffuse large B-cell lymphoma. Methods. A total of 2647 patients diagnosed with primary gastric diffuse large B-cell lymphoma from 1998 to 2014 were extracted from SEER database. Propensity matching was performed to compare the clinicopathological characteristics of the two groups. Based on the recursive partitioning analysis, the patients were divided into three risk subgroups: low risk, intermediate risk, and high risk. Results. After propensity score matching, patient characteristics did not differ significantly between the two groups. The 5-year cancer-specific survival rates of the surgical group and the conservative treatment group were, respectively, 60% and 59.2% (P=0.952) before propensity matching and 64.2% and 58.6% (P=0.046) after propensity matching. According to the multivariate analysis, age, tumor stage, and chemotherapy and surgery were independent risk factors for long-term survival. The 5-year cancer-specific survival rates differed significantly between the low-risk, intermediate-risk, and high-risk patients (76.2% vs. 57.4% vs. 25.5%, respectively, P0.05). Conclusions. A prognostic model was constructed based on the independent risk factors of age, tumor stage, and chemotherapy. The prognostic model indicated that low-risk patients (age

Objective. To investigate the validity of the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer. Methods. The clinicopathologic data of 7371 patients who were diagnosed with gastric cancer and had 16 or more involved lymph nodes (LNs) were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and retrospectively reviewed. Results. Stage migration occurred primarily during stage III between the 7th and 8th edition TNM staging systems. Stages IIIB and IIIC in the 7th edition staging system were divided in the 8th edition and had obvious differences in survival rates (both P